Developing a Lipopolysaccharide vaccine against meningitis B bacteria
Professor Richard Moxon, University of Oxford
One in 10 people have the meningitis-causing bacteria living harmlessly in the back of their noses and throats. During this study, Professor Moxon and his team examined what causes the bacteria to suddenly become harmful and cause meningitis and septicaemia.
Meningococcal bacteria come in different forms called serogroups, where each serogroup has a different outer coat surrounding them. Currently available vaccines only protect against individual serogroups, for example, the vaccine against Meningitis C. However, for serogroup B, which is responsible for the most common form of bacterial meningitis and meningococcal septicaemia in the UK - Meningitis B, there is still no vaccine.
This study aimed to investigate the potential for developing a vaccine that contained lipopolysaccharide, part of the bacterial capsule. Initially, researchers needed to isolate the lipopolysaccharide structure and identify a consistent part of the molecule that does not change between strains. Researchers then assessed whether they could produce antibodies that would bind to this molecule.
Researchers may be able to develop a vaccine against Neisseria meningitidis type B that is based on the trunk of the lipopolysaccharide molecule found on the surface of these bacteria.
This project is now complete - see the outcomes tab for more information.
This study focused on purifying a molecule known as Lipopolysaccharide (LPS), which is found on the outer coat of the meningococcal bacteria in all strains - regardless of their serogroup - so could make a good vaccine candidate. LPS is a molecule with a tree-like structure that has ‘roots' anchoring it to the bacteria, a ‘trunk' that forms its core and ‘branches' formed of chains of sugar molecules. While the trunk remains the same, the bacteria can make branches that vary from one bacterium to another, which makes it difficult for the immune system to recognise. Professor Moxon and his team found a way to overcome this by focusing on the trunk, which always looks the same. By turning off the genes responsible for making the branches, they were able to generate antibodies to the trunk.
The team succeeded in generating three types of antibodies to LPS trunk structures, which are able to recognise 98% of meningococcal strains, although not all of the antibodies are able to kill the bacteria. The next stage of the study is to find a structure, which when used in a vaccine, will allow the immune system to recognise the bacteria, no matter how it changes its branches, and kill the bacteria before it has the chance to damage the body.
Development of a Lipopolysaccahride-based conjugate vaccine to prevent Neisseria meningitides serogroup B invasive disease
Professor Richard Moxon, University of Oxford
One in 10 people have the meningitis-causing bacteria living harmlessly in the back of their noses and throats. During this study, Professor Moxon and his team examined what causes the bacteria to suddenly become harmful and cause meningitis and septicaemia.
Meningococcal serogroups and strains vary in their capsule composition, making it hard to develop a vaccine that induces cross-reactive immunity against different serogroups and strains, especially against strains of the type B meningococcus.
Lipopolysaccaride (LPS) on the surface of bacterial cells has a consistent inner core and varies only in the composition of its sugar extensions. Potentially, antibodies against the inner core of LPS could provide immunity against a range of Neisseria meningitidis bacteria, independent from the composition of sugar molecules attached to the LPS core structure.
Studies have shown that antibodies against LPS core components exist in healthy adults. These antibodies need to be studied further in order to identify the parts of the inner core structure that elicit the most potent immune response and could be suitable as vaccine candidates.
The aim of this study is to develop an inner core lipoposlysaccharide (LPS) vaccine to elicit high affinity long-lasting protective antibodies against Neisseria meningitidis serogroup B in infants, children and adults.
To achieve this, the team first tested murine antibodies against LPS core structures to determine their ability to bind and kill bacteria. They then purified anti-LPS antibodies from human serum and determine functional activity of these antibodies in vitro and in vivo. Finally, they tested candidate LPS conjugate vaccines in adult mice and rabbits to investigate safety, immunogenicity and ability to induce functional antibodies to protect against MenB disease in animals.
This project is now complete - see the outcomes tab for more information.
The researchers showed that murine antibodies were able to bind to the bacterial cell surface, but unfortunately two of three antibodies did not exhibit any bactericidal activity in vitro.
Antibodies isolated from human sera showed some ability to bind specific mutant strains (designed to catch these antibodies specifically) and mutants carrying fully extended modified LPS (lacking a sugar in the inner core region). They also showed some ability to protect infant rats through passive immunisation, as two of three antibodies reduced bacteraemia when challenged with the corresponding mutant strains, but not the fully extended modified strain. These experiments have demonstrated that antibodies are produced by normal, healthy humans to specific inner core LPS structures and also, importantly, are bactericidal to MenB carrying homologous LPS structures.
The researchers then tested new Neisseria meningitidis inner core LPS conjugate vaccines in mice and rabbits. Responses to the vaccines varied between animals, but those that did respond showed a strong immune reaction to the immunising carbohydrate antigen. Unfortunately, protection achieved through the vaccine in rats and rabbits was low against wild type strains (with fully extended, non-modified LPS). However, some evidence for functional activity against mutants with fully extended modified LPS (lacking a sugar in the inner core region) was found in vitro and in infant rats through passive protection. Current studies aim to develop a methodology for preparing conjugate vaccines that contain fully extended non-modified LPS (with the sugar molecule in the inner core region), to induce immune responses that can protect from wild type infection.
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